Current neuroendocrine studies focus on elucidating normal physiology and pathophysiological mechanisms in controls and patients with major psychiatric and neuroendocrine diseases. Our studies with corticotropin releasing hormone (CRH) suggest that this peptide functions as a physiologically relevant stimulus to the pituitary-adrenal axis in man. Hence, eight 1 Mug/kg pulses of human CRH (hCRH) given over 24 hours in a temporal sequence designed to mimic naturally occurring ACTH pulses, restored the normal pulse frequency and amplitude of ACTH and cortisol secretion in patients with hypothalamic CRH deficiency. This study also showed that the ACTH response to hCRH was enhanced in the early morning, suggesting that the pituitary corticotroph cell shows a circadian rhythm in its response to CRH. This idea is supported by our finding in volunteers that the early morning cortisol surge is associated with an increase in both the pulse frequency and the amplitude of ACTH secretory episodes. Our previous suggestion that hypercortisolism in depression reflects hypersecretion of CRH is supported by data that abnormally high post-dexamethasone plasma ACTH levels in depression are negatively correlated with CSF CRH. In addition, our previous suggestion that the hypothalamic CRH neuron in Cushing's disease is normally suppressed by long-standing hypercortisolism is supported by data that CSF CRH is markedly reduced in this disorder. In an enlarged series of depressed and Cushing's disease patients, the CRH stimulation test remains helpful in their differential diagnosis. In patients with anorexia nervosa, responses to CRH stimulation and an elevation in CSF CRH suggest that the hypercortisolism in this disorder reflects the hypersecretion of endogenous CRH. A second study in anorexia nervosa utilizing growth hormone-releasing hormone shows that the hypersecretion of GH in this disorder reflects a somatomedin deficiency, secondary either to hypercortisolism or chronic inanition. Other findings include decreased CSF CRH and ACTH in Alzheimer's disease unassociated with hyperfunction of the pituitary-adrenal axis.